The East African highlands (>1,500 m above sea level) used to be free of malaria. However, since 1988 malaria epidemics have frequently occurred in some highland areas, causing hundreds or even thousands of deaths. In 1999, malaria outbreaks occurred in more than 20 highland sites in Kenya alone. The causes of the recent reemergence of Plasmodium falciparum epidemic malaria are controversial. One (1) hypothesis is that malaria parasites in the highlands come from surrounding malaria endemic lowland area, and widespread antimalarial drug resistance causes treatment failure and thus induces an epidemic. The molecular epidemiology of drug resistance and Plasmodium genetic structure in the highlands are unknown, but this information is essential for a comprehensive understanding of the emergence of highland malaria. The current proposal will test this hypothesis through comparison of P. falciparum population genetic diversity between highlands and lowlands, and prior to an epidemic and in the peak of an epidemic. 3 types of molecular markers will be used, including the genes coding for merozoite surface protein 1 and 2, polymorphic microsatellites and P. falciparum dihydrofolate reductase (DHFR) gene mutations known to confer resistance to antimalarial drug sulfadoxine-pyrimethamine. The proposed research will determine if highland malaria parasites are less diverse than lowland parasites, and whether highland malaria outbreaks result from the spread of drug-resistant parasite populations from lowland areas or from locally persistent low-level infections. The proposed research will contribute to building research capacity in Kenya by training 1 Kenyan Ph.D. student and establishing a PCR facility for parasite genotyping and drug resistance molecular diagnosis. This research will be conducted as an extension of NIH grant R01 AI50243-04.